PROJECT SUMMARY/ABSTRACT The major goal of this RC2 proposal is to generate the first, multi-omics translational study capturing the sum of environmental exposures (i.e. the exposome) and comprehensive data resource for Primary Sclerosing Cholangitis (PSC), a chronic, progressive liver disease without effective medical therapy. PSC shortens survival, is associated with inflammatory bowel disease (IBD) and strongly predisposes to cholangiocarcinoma (i.e. bile duct cancer) and colon cancer. Our recent genome wide association studies (GWAS) revealed the significant role of genetic variation in PSC, while also re-emphasizing the importance of environmental factors and gene-environment interactions in PSC pathogenesis. To further elucidate the role of exposures from our external environment and lifestyle (e.g., diet, stress, toxins, drugs, microbes), we have assembled a world-class, multi-disciplinary team that synergizes expertise and resources across four institutions: Mayo Clinic, Emory University, University of Illinois Urbana-Champaign (UIUC), and University of Oslo, Norway. Our collaborative team will leverage large clinical databases and biorepositories, as well as expertise in PSC and related conditions, exposomics, metabolomics, methylomics, transcriptomics, metagenomics, genomics, and data analytics to develop the PSC Scientific Community Resource for hypothesis-generating science and simultaneously uncover factors contributing to PSC. We now seek to define the bigger-picture cellular networks, rather than individual genes, driving disease processes. To do so, we will use unbiased network-based approaches designed to integrate multiple layers of omics data. Our proposal is predicated on the hypothesis that multi-omics analyses of data capturing environmental exposures and the associated biological responses, including the effect on the genome, will reveal networks or pathways influencing PSC pathogenesis and outcomes. To test this hypothesis, we will perform a series of sophisticated analyses to identify PSC-associated changes in and across the exposome, metabolome, methylome, and transcriptome in blood as well as the gut metagenome, exposome and metabolome. Our collaboration and data generation are already underway with pilot studies demonstrating differences in blood exposomes and metabolomes and stool metagenomes between PSC patients and controls. Using a suite of bioinformatic tools and available genetic variation data, we aim to discover stable, detectable, omics-based disease signatures in blood (Aim 1) and stool (Aim 2) that when integrated with clinical data (Aim 3) will reveal biological pathways driving disease pathogenesis and outcomes. All data, residual specimens, and analytical details will be made freely available to the research community in accordance with NIDDK's mission. Furthermore, this effort responds to the NIDDK's call ?to better understand the role of the microbiome, genetics, and exposome.?